1,4-substitued 4,4-diaryl cyclohexanes

ABSTRACT

This invention relates to compounds of Formula (I) where Z is an amine, alcohol or derivative thereof, and the ketone analog thereof.

This application is a 371 of PCT/US00/21867 filed Aug. 10, 2000 whichclaims benefit of Provisional Serial No. 60/148,034 filed Aug. 10, 1999.

AREA OF THE INVENTION

This invention relates to compounds which are PDE4 inhibitorsparticularly in regards to treating allergic and inflammatory diseasesand for inhibiting the production of Tumor Necrosis Factor (TNF). Theyare particularly use for treating pulmonary diseases such as variousforms of asthma and chronic obstructive pulmonary disease.

BACKGROUND OF THE INVENTION

The compounds of this invention can be used in treating conditions whichare modulated by the inhibition of PDE4. They have particularapplication in regards to treating allergic and inflammatory diseasesand for inhibiting the production of Tumor Necrosis Factor (TNF).

As regards anti-inflammatory activity, one target disease is chronicobstructive pulmonary disease (COPD). COPD is an umbrella termfrequently used to describe two conditions of fixed airways disease,chronic bronchitis and emphysema. Chronic bronchitis and emphysema aremost commonly caused by smoking; approximately 90% of patients with COPDare or were smokers. Approximately 50% of smokers develop chronicbronchitis, and about 15% of smokers develop disabling airflowobstruction. The airflow obstruction associated with COPD isprogressive, may be accompanied by airway hyperactivity, and may bepartially reversible. Non-specific airway hyper-responsiveness may alsoplay a role in the development of COPD and may be predictive of anaccelerated rate of decline in lung function in smokers.

Another disease treatable with PDE4 inhibitors is asthma, particularlyasthma caused by extrinsic stimuli. It is a complex, multifactorialdisease characterized by reversible narrowing of the airway andhyperactivity of the respiratory tract to external stimuli. Multiplemediators are responsible for the development of asthma. It seemsunlikely that eliminating the effects of a single mediator will have asubstantial effect on all three components of chronic asthma. Analternative to the “mediator approach” is to regulate the activity ofthe cells responsible for the pathophysiology of the disease. One suchway is by elevating levels of cAMP (adenosine cyclic3′,5′-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺²-ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE 4, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,“Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd,1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells. basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE 4 inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE 4inhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of tumornecrosis factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis.osteoarthritis, gouty arthritis and other arthritic conditions: sepsis.septic shock. endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), ARC (AIDSrelated complex). keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, auto-immune diabetesand systemic lupus erythematosis.

This invention provides compound which are useful in treating thesediseases, and others modulated by PDE4, by inhibiting one or more of thevarious isoforms of PDE4.

SUMMARY OF THE INVENTION

In a first aspect this invention relates to a compound of Formula(I)

wherein:

R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or —(CR₄R₅)_(r)R₆ wherein the alkyl moietiesunsubstituted or substituted with one or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆;

X is YR₂, fluorine, NR₄R₅, or formyl amine;

Y is O or S(O)_(m′),

m′ is 0, 1, or 2;

X₂ is O or NR₈;

X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(0)NR₈R₈, or NR₈R₈;

R₂ is independently selected from —CH₃ or —CH₂CH₃ optionally substitutedby 1 or more halogens;

s is 0 to 4;

Ar is phenyl unsubstituted or substituted by R₇;

Z is OR₁₄, OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉,NR₁₀C(Y′)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄,orNR₁₀C(O)C(O)OR₁₄;

Y′ is O or S;

R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein: the R₁₂ or C₁₋₆ alkyl groupis unsubstituted or substituted one or more times by methyl or ethylunsubstituted or substituted by 1-3 fluorines; —F; —Br; —Cl; —NO₂;—NR₁₀R₁₁; —C(O)R₈; —CO₂R₈; —O(CH₂)₂₋₄OR₈; —O(CH₂)_(q)R₈; —CN;—C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)R₉;—NR₁₀C(O)NR₁₀R₁₁; —NR₁₀C(O)R₁₁; —NR₁₀C(O)OR₉; —NR₁₀C(O)R₁₃;—C(NR₁₀)NR₁₀R₁₁; —C(NCN)NR₁₀R₁₁; —C(NCN)SR₉; —NR₁₀C(NCN)SR₉;—NR₁₀C(NCN)NR₁₀R₁₁; —NR₁₀S(O)₂R₉; —S(O)_(m′)R₉; —NR₁₀C(O)C(O)NR₁₀R₁₁;—NR₁₀C(O)C(O)R₁₀; or R₁₃;

q is 0, 1, or 2;

R₁₂ is R₁₃, OR₁₄, OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄,NR₁₄C(O)R₉, NR₁₀C(Y′)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄,NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄,NR₁₀C(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄,NR₁₀C(O)C(O)NR₁₀R₁₄, or NR₁₀C(O)C(O)OR₁₄; or C₃-C₇ cycloalkyl, or (2-,3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl),pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or3-thienyl), quinolinyl, naphthyl, or phenyl, wherein each of (2-, 3- or4-pyridyl), pyrimidinyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl),quinolinyl, naphthyl, or phenyl may be substituted by OR₁₄, OR₁₅, SR₁₄,S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(Y′)R₁₄,NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄,NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉,NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, or NR₁₀C(O)C(O)OR₁₄;

R₈ is independently selected from hydrogen or R₉;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups unsubstituted or substitutedon the methyl with 1 to 3 fluoro atoms;

R₁₄ is hydrogen or R₇; or when R₈ and R₁₄ are as NR₈R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₈R₁₄, S(O)_(q)NR₈R₁₄ or S(O)_(q)R₇ where q is 0, 1or 2;

provided that:

(f) R₇ is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines;

or the pharmaceutically acceptable salts thereof.

In addition this invention covers the 1-position ketones analogous toFormula (I), namely compounds of Formula (II)

wherein the various groups on Formula (II) other than Z are the same asfor Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I) and (II).

Phosphodiesterase 4 inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE 4 inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I). Such viruses include, but are not limited toHIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus andthe Herpes group of viruses, such as, but not limited to, Herpes zosterand Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I) and (II) The compounds of thisinvention may also be used in association with the veterinary treatmentof animals, other than in humans, in need of inhibition of TNFproduction. TNF mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedabove, but in particular viral infections. Examples of such virusesinclude, but are not limited to feline immunodeficiency virus (FIV) orother retroviral infection such as equine infectious anemia virus,caprine arthritis virus, visna virus, maedi virus and otherlentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) and (II) may be administered in conjunctionwith other drugs of choice for systemic yeast and fungal infections.Drugs of choice for fungal infections, include but are not limited tothe class of compounds called the polymixins, such as Polymycin B, theclass of compounds called the imidazoles, such as clotrimazole,econazole, miconazole, and ketoconazole: the class of compounds calledthe triazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The compounds of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)and (II) to a mammal in need of such treatment. Preferably, a compoundof Formula (I) and (II) is administered for inhibiting or reducing thetoxicity of the Amphotericin class of compounds, in particularAmphotericin B.

“Inhibiting the production of IL-1” or “inhibiting the production ofINF” means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

The phrase “TNF mediated disease or disease states” means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as “TNF”unless specifically delineated otherwise. Preferably TNF-α is inhibited.

“Cytokine” means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, this cytokine is TNF-α.

Pharmaceutically acceptable salts of the instant compounds, where theycan be prepared, are also intended to be covered by this invention.These salts will be ones which are acceptable in their application to apharmaceutical use. By that it is meant that the salt will retain thebiological activity of the parent compound and the salt will not haveuntoward or deleterious effects in its application and use in treatingdiseases.

Pharmaceutically acceptable salts are prepared in a standard manner. Theparent compound, dissolved in a suitable solvent, is treated with anexcess of an organic or inorganic acid, in the case of acid additionsalts of a base, or an excess of organic or inorganic base where themolecule contains a COOH for example.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theFormula (I) and (II). The compound may be present in an amount to effecta physiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the composition toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, aerosols, and dropssuitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on the therapeutic actionof the instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

In these compositions, the amount of carrier or diluent will vary butpreferably will be the major proportion of a suspension or solution ofthe active ingredient. When the diluent is a solid it may be present inlesser, equal or greater amounts than the solid active ingredient.

Usually a compound of Formula I is administered to a subject in acomposition comprising a nontoxic amount sufficient to produce aninhibition of the symptoms of a disease in which leukotrienes are afactor. Topical formulations will contain between about 0.01 to 5.0% byweight of the active ingredient and will be applied as required as apreventative or curative agent to the affected area. When employed as anoral, or other ingested or injected regimen, the dosage of thecomposition is selected from the range of from 1 mg to 1000 mg of activeingredient for each administration. For convenience, equal doses will beadministered 1 to 5 times daily with the daily dosage regimen beingselected from about 1 mg to about 5000 mg.

Preferred compounds of either Formula (I) or (II) are as follows:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties—CF₃, —CH₂F, —CHF₂, —CF₂CHF₂, —CH₂CF₃, and —CH₂CHF₂. Preferred R₁substitutents for the compounds of Formula (I) are CH₂-cyclopropyl,CH₂-C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl unsubstituted or substituted withOH, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl unsubstituted or substitutedby 1 or more fluorines, —(CH₂)₁₋₃C(O)O(CH₂)₀₋₂CH₃,—(CH₂)₁₋₃O(CH₂)₀₋₂CH₃, and —(CH₂)₂₋₄OH.

When R₁ term contains the moiety (CR₄R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄R₅)_(n) or (CR₄R₅)_(m); each repeatingmethylene unit is independent of the other, e.g., (CR₄R₅)_(n) wherein nis 2 can be —CH₂CH(—CH₃)—, for instance. The individual hydrogen atomsof the repeating methylene unit or the branching hydrocarbon canunsubstituted or be substituted by fluorine independent of each other toyield, for instance, the preferred R₁ substitutions, as noted above.When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0^(2,6)]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published Nov. 5, 1987.

Z is preferably OR₁₄, OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄,NR₁₄C(O)R₉, NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, orNR₁₀C(O)C(O)OR₁₄.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkylunsubstituted or substituted by 1 or more halogens. The halogen atomsare preferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a —CF₃,—CHF₂, or —CH₂CHF₂ moiety. Most preferred are the —CHF₂ and —CH₃moieties.

Preferred R₇ moieties include unsubstituted or substituted—(CH₂)₁₋₂(cyclopropyl), —(CH₂)₀₋₂(cyclobutyl), —(CH₂)₀₋₂(cyclopentyl)unsubstituted or substituted by OH, —(CH₂)₀₋₂(cyclohexyl), —(CH₂)₀₋₂(2-,3- or 4-pyridyl), (CH₂)₁₋₂(2-imidazolyl), (CH₂)₂(4-morpholinyl),(CH₂)₂(4-piperazinyl), (CH₂)₁₋₂(2-thienyl), (CH₂)₁₋₂(4-thiazolyl), and(CH₂)₀₋₂phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety —NR₁₀R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety —NR₁₀R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but is not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is unsubstituted or substituted by a heterocyclic ringsuch as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be unsubstituted or substituted by R₈either on an available nitrogen or carbon atom, such as1-(R₈)-2-imidazolyl, 1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl,1-(R₈)-3-pyrazolyl, 1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl,1-(R₈)-4-triazolyl, or 1-(R₈)-5-triazolyl. Where applicable, the ringmay be substituted one or more times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is—CH₂-cyclopropyl, —CH₂—C₅₋₆ cycloalkyl, —C₄₋₆ cycloalkyl unsubstitutedor substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl),benzyl or —C₁₋₂ alkyl unsubstituted or substituted by 1 or morefluorines, and —(CH₂)₂₋₄ OH; R₂ is methyl or fluoro-substituted alkyl,and X is YR₂.

Most preferred are those compounds wherein R₁ is —CH₂-cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂H; X is YR₂; Y isoxygen; X₂ is oxygen; and R₂ is CF₂H or methyl.

The most perferred compounds are:

4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone;

cis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol;

trans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine;

cis-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine;and

trans-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine.

The following examples are given to further illustrate the describedinvention. These examples are intended solely for illustrating theinvention and should not be read to limit the invention in any manner.Reference is made to the claims for what is reserved to the inventorshereunder.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

Compounds of the Formula I can be prepared by methods described inScheme 1.

Scheme 1

3-Cyclopentyloxy-4-methoxybenzaidehyde, 3-Scheme-1, can be prepared from3-hydroxy-4-methoxybenzaldehyde, 1-Scheme-1, by alkylation withcyclopentyl bromide, 2-Scheme-1, in the presence of potassium carbonateor other suitable base with DMF as one of several suitable solventsaccording to published methods (J. Med. Chem. 1999, 41, 821-835; U.S.Pat. No. 4,012,495, Mar. 15, 1977). Arylation of 3-Scheme-1 using, e.g.,4-bromophenyl lithium (prepared by treatment of 1,4-dibromobenzene withbutyl lithium) in THF provides4′-bromo-4-cyclopentyloxy-3-methoxybenzhydrol, 4-Scheme-1, which can beoxidized to 4′-bromo-4-cyclopentyloxy-3-methoxybenzophenone, 5-Scheme-1,using, e.g., manganese dioxide in dichlomethane. Homologation of5-Scheme-1 can be accomplished by treatment withα-chloro-α-trimethylsilylmethyllithium (prepared by treatment ofchloromethyltrimethylsilane with sec-butyllithium andtetramethylethylenediamine in THF) to afford the α,β-epoxysilane6-Scheme-1. Hydrolysis of 6-Scheme-1 by treatment with TFA indichlomethane provides2-(4-bromophenyl)-2-(3-cyclopentyloxy-4-methoxyphenyl) acetaldehyde,7-Scheme-1. Robinson annulation of 7-Scheme-1 using methyl vinyl ketonewith potassium hydroxide in ethanol provides4-(4-bromophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cylohex-2-en-1-one, 8-Scheme-1. Suzuki coupling of 8-Scheme-1 with2-(2-aminopyrimidin-5-yl)-4,4,5,5-tetramethyl-1,3-dioxaborolane[prepared from 2-amino-5-iodo pyrimidine by treatment withbis(pinacolato)diboron and1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)] usingtetrakis(triphenylphosphene)palladium(0) with sodium carbonate intoluene, provides4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-2-en-1-one, 9-Scheme-1. This is reduced first to4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone,10-Scheme-1, by hydrogenation using catalytic palladium on carbon.Subsequent reduction of the ketone by sodium borohydride in methanolaffords a cis- and trans-mixture of4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol,11-Scheme-1. The cis- and trans-isomers can be separated by flashchromatography, then carried through the remainder of the synthesisindependently. Independent Mitsunobu reaction of cis-Scheme-1 andtrans-11-Scheme-1 using phthalimide with triphenylphosphine anddiisopropyl azodicarboxylate, followed by hydrolysis with hydrazinemonohydrate in ethanol, yields, respectively, trans- andcis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine,trans-12-Scheme-1 and cis-12-Scheme-1.

The following examples are given to illustrate the invention. They arenot intended to limit the invention in any fashion.

EXAMPLES Example 1 3-Cyclopentyloxy-4-methoxybenzaldehyde

A suspension of 3-hydroxy-4-methoxybenzaldehyde (30 g, 0.2 mol),cyclopentyl bromide (35.77 g, 0.24 mol) and potassium carbonate (38.6 g,0.28 mol) in N,N-dimethylformamide (200 ml) was stirred vigorously forthree days. Water (300 ml) was added and the mixture was extracted fourtimes with ethyl acetate. The combined organic extract was washed threetimes with 10% aqueous sodium hydroxide solution, once with water, oncewith brine, dried (sodium sulfate) and evaporated to provide the titlecompound as a clear orange oil (36.47 g, 83%). ¹H-NMR (400 MHz, CDCl₃):δ 9.84 (s, 1H), 7.43 (dd, 1H, J=8.3 Hz, 1.8 Hz), 7.39 (d, 1H, J=1.8 Hz),6.96 (d, 1H, J=8.3 Hz), 4.86 (m, 1H), 3.93 (s, 3H), 2.0 (m, 2H),1.8-1.95 (m, 4H), 1.63 (m, 2H)

Example 2 4′-Bromo-4-cyclopentyloxy-3-methoxybenzhydrol

To a solution of 1,4-dibromobenzene (25.72 g, 109 mmol) in drytetrahydrofuran (50 ml) at isopropanolg/dry ice bath temperature underargon was added n-butyl lithium (43.6 ml of 2.5 M solution in hexane,109 mmol) dropwise. This was stirred for one hour during which time aslurry formed. This slurry was added via cannula to a solution of3-cyclopentoxy-4-methoxybenzaldehyde (20.0 g, 90.8 mmol) in dry THF (140ml) at isopropanol/dry ice bath temperature. After one hour, thereaction was allowed to gradually warm to room temperature and stirredfor an additional 4 h. The reaction was quenched with water thenextracted three times with diethyl ether. The combined organic extractwas washed successively with 1% hydrochloric acid, water, brine, thendried and evaporated. Purification by flash chromatography (silica gel,17% ethyl acetate/83% hexane) provided the title compound as a palewhite solid (36.78 g, 100% crude yield). MS (m/e): 359 [(M+1H₂O)⁺]

Example 3 4′-Bromo-4-cyclopentyloxy-3-methoxybenzophenone

To a solution of 4′-bromo-4-cyclopentoxy-3-methoxybenzhydrol (10 g 0.5mmol) in dichloromethane(50 ml), was added manganese (IV) oxide (24.0 g,267 mmol). The mixture was stirred at the room temperature for two daysthen filtered through celite and the residue washed withdichloromethane. The filtrate was evaporated and the residuecrystallized from ethanol to afford the title compound as a white solid(8.2 g, 83%). MS (m/e): 375 [(M+1)⁺].

Example 42-(4-Bromophenyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)acetaldehyde

Chloromethyltrimethylsilane (1.875 g, 15.37 mmol) in dry THF (45 ml) at−78° C. was treated with sec-butyllithium (13.0 ml of 1.3 M solution incyclohexane, 16.88 mmol) followed by TMEDA (2.4 ml, 16.1 mmol). Themixture was stirred for 40 min, then warmed to −55° C.4′-Bromo-4-cyclopentoxy-3-methoxybenzophenone (4.0 g, 10.6 mmol) in THF(20 ml) was added and the mixture stirred at −40° C. for 0.5 h. It wasthen warmed to room temperature gradually and stirred for an additional18 h. The reaction was quenched with aqueous ammonium chloride solutionand the resultant mixture extracted three times with ethyl acetate. Thecombined organic extract was washed with water then brine, dried (sodiumsulfate) and evaporated. The residue was purified by flashchromatography (silica gel, 4% ethyl acetate/96% hexane). The resultingyellow oil was stirred in 50 ml of 20% trifluoroacetic acid indichlomethane for one hour then washed three times with water, once withdilute sodium bicarbonate, twice with water, once with brine and dried(sodium sulfate). The solvent was evaporated to provide the titlecompound as a yellow oil (1.757 g, 42.5%). ¹H-NMR (400 MHz, CDCl₃): δ9.87 (s, 1H), 7.49 (d, 2H, J=8.4), 7.07 (d, 2H, J=8.4), 6.87 (d, 1H,J=8.2), 6.70 (dd, 1H, J=2.2, J=8.3), 6.68 (d, 1H, J=2.2).

Example 54-(4-Bromophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cylohexen-1-one

To a solution of 2-(4-bromophenyl)-2-(3-cyclopentyloxy-4-methoxyphenyl)acetaldehyde (2.60 g, 6.7 mmol) in THF (10 ml) was added methyl vinylketone (670 ul, 8.4 mmol). The solution was stirred at −10° C. and 10%ethanolic potassium hydroxide (480 ul) was added slowly. After 0.5 h thereaction mixture was warmed to room temperature and stirred foradditional 1 h. Water and ethyl acetate were added and the mixture wasneutralized with 3N hydrochloric acid. The layers were separated and theaqueous layer washed twice with ethyl acetate. The combined organicextract was washed with water then brine, dried (sodium sulfate) andevaporated. Purification by flash chromatography (silica gel, 12% ethylacetate/82% hexane) provided the title compound as a pale white waxysolid (1.39 g, 47%). MS (m/e): 441 [(M+1)⁺], 443 [(M+3)⁺].

Example 64-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cyclohexen-1-one

To a solution of4-(4-bromophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cylohexen-1-one(1.39 g, 3.17 mmol) in Toluene (50 ml) was addedtetrakis(triphenylphosphine)palladium(0) (417 mg, 0.36 mmol), followedby 2-(2-aminopyrimidin-5-yl)-4,4,5,5-tetramethyl-1,3-dioxaborolane (2.02g, 6.1 mmol, prepared as described in Tatsuo Ishiyama; Miki Murata andNorio Miyaura, J. Org. Chem. 1995, 60, 7508-7510), ethanol (8 ml) and 2Msodium carbonate (8 ml). The reaction mixture was stirred under argon at80° C. for 18 h. Water was added and the mixture extracted three timeswith ethyl acetate, the combined organic extract was washed with waterthen brine, dried (sodium sulfate) and evaporated. Purification by flashchromatography (silica gel, 73% ethyl acetate/27% hexane) provided thetitle compound as a white solid (1.2 g, 83% crude yield). MS (m/e): 456[(M+1)⁺].

Example 74-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone

A slurry of4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-cyclohexen-1-one(1.2 g, 2.63 mmol) in ethyl acetate (20 ml) with palladium on activatedcarbon (360 mg, 30% w/w) was stirred under hydrogen at atmosphericpressure for three days then filtered and the residue washed withdichloromethane. The combined organic solution was evaporated to affordthe title compound as a gray solid (1.05 g, 88% crude yield). ¹H-NMR(400 MHz, CDCl₃): δ 8.51 (s, 2H), 7.44 (d, 2H, J=8.4), 7.38 (d, 2H,J=8.4), 6.89 (dd, 1H, J=8.4, J=2.2), 6.84 (d, 1H, J=8.4), 6.83 (d, 1H,J=2.2), 5.21 (s, 2H), 4.69 (m, 1H), 3.83(s, 3H), 2.64 (m, 4H), 2.48 (m,4H). 1.81 (m, 6H), 1.57 (m, 2H).

Example 84-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol

Sodium borohydride (86.6 mg, 2.29 mmol) was added to a slurry of4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone(1.05 g, 2.29 mmol) in methanol (50 ml) and tetrahydrofaran (12.5 ml).The mixture was stirred for 1.5 h (the slurry became a clear solutionafter 10 min). Acetone was added to destroy the excess sodiumborohydride and all the solvent was removed. The residue was evaporatedtwice from methanol then dissolved in ethyl acetate and washed withwater then brine and dried (sodium sulfate). Evaporation of solventfollowed by purification by flash chromatography (silica gel, 5%methanol/95% dichloromethane) providedcis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanolas a white solid (485 mg, 46%). MS (m/e): 460 (M+1)⁺; andtrans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanolas a white solid (458 mg, 43%), MS (m/e): 460 (M+1)⁺.

Example 9Trans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine

To a solution ofcis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol(462 mg, 1.01 mmol) in THF (15 ml) was added triphenylphosphine (1.318g, 5.58 mmol), phthalimide (740 mg, 5.58 mmol) and diisopropylazodicarboxylate (1.0 ml, 5.58 mmol). This was stirred for 18 h thensolvent was removed. The residue was purified by flash chromatography(silica gel, 3% methanol/97% dichiromethane) and the resulting crudetrans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-phthalimido-cyclohexane[MS(m/e):589 (M⁺+1)] was used without farther purification.

To a solution oftrans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-phthalimido-cyclohexane(crude product from previous step) in ethanol (20 ml) was addedhydrazine monohydrate (2.0 ml) and the resulting solution was heated toreflux for 4 h. The solvent was removed and the residue dissolved inethyl acetate then washed with 3N hydrochloric acid three times. Thecombined aqueous extract was washed with ethyl acetate once thenneutralized with 10% aqueous sodium hydroxide solution and extractedfour times with ethyl acetate. The combined organic extract was washedwith water, brine then dried (sodium sulfate) and solvent removed invacuo. Purification by flash chromatography (silica gel, 5% methanol/94%dichlromethane/1% ammonium hydroxide) followed by preparative HPLCprovided the title compound as a white solid (120 mg, 26%). MS (m/e):459 [(M+1)⁺].

Example 10Cis-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine

The title compound was prepared following the procedure in (9) exceptsubstitutingtrans-4-[4-(2-amninopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanolforcis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol.Purification by flash chromatography (silica gel, 5% methanol/94%dichlromethane/1% ammonium hydroxide) followed by preparative HPLCprovidedcis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amineas a white solid (120 mg, 41%). MS (m/e): 459 [(M+1)⁺].

UTILITY EXAMPLES Example A Inhibitory Effect of Compounds of Formula (I)and (II) on In Vitro TNF Production by Human Monocytes

The inhibitory effect of compounds of Formula (I) and (II) on in vitroTNF production by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

Example B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I) and (II). The protocolused in these models is described in Badger et al., EPO publishedApplication 0 411 754 A2, Feb. 6, 1991, and in Hanna. WO 90/15534, Dec.27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

Example C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) and (II) can be determined using a battery offive distinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called “Ia”), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques [Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. PositiveIC_(50's) in the nanomolar to μM range for compounds of the workingsexamples described herein for Formula (I) and (II) have beendemonstrated.

What is claimed is:
 1. A compound of Formula(I)

wherein: R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties unsubstituted or substitutedwith one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ andR₅ are independently selected hydrogen or C₁₋₂ alkyl; R₆ is hydrogen,methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃ alkyl, halosubstituted aryloxyC₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup; provided that: a) when R₆ is hydroxyl, then m is 2; or b) when R₆is hydroxyl, then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆; X is YR₂, fluorine, NR₄R₅, or formyl amine;Y is O or S(O)_(m′), m′ is 0, 1, or 2; X₂ is O or NR₈; X₄ is H, R₉, OR₈,CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈; R₂ is independently selectedfrom —CH₃ or —CH₂CH₃ optionally substituted by 1 or more halogens; s is0 to 4; Ar is phenyl unsubstituted or substitued by R₇; Z is OR₁₄, OR₁₅,SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(Y′)R₁₄,NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄,NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉, NR₁₀C(CR₄NO₂(SR₉,NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, or NR₁₀C(O)C(O)OR₁₄; Y′ is O orS; R₇ is —(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein: the R₁₂ or C₁₋₆ alkylgroup is unsubstituted or substituted one or more times by methyl orethyl unsubstituted or substituted by 1-3 fluorines; —F; —Br; —Cl; —NO₂;—NR₁₀R₁₁; —C(O)R₈; —CO₂R₈; —O(CH₂)₂₋₄OR₈; —O(CH₂)_(q)R₈; —CN;—C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)₉;—NR₁₀C(O)NR₁₀R₁₁; —NR₁₀C(O)R₁₁; —NR₁₀C(O)OR₉; —NR₁₀C(O)R₁₃;—C(NR₁₀)NR₁₀R₁₁; —C(NCN)NR₁₀R₁₁; —C(NCN)SR₉; —NR₁₀C(NCN)SR₉;—NR₁₀C(NCN)NR₁₀R₁₁; —NR₁₀S(O)₂R₉; —S(O)_(m′)R₉; —NR₁₀C(O)C(O)NR₁₀R₁₁;—NR₁₀C(O)C(O)R₁₀; or R₁₃; q is 0, 1, or 2; R₁₂ is R₁₃, OR₁₄, OR₁₅, SR₁₄,S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(Y′)R₁₄,NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄,NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉,NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, or NR₁₀C(O)C(O)OR₁₄; or C₃-C₇cycloalkyl, or (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl,(2- or 3-thienyl), quinolinyl, naphthyl, or phenyl, wherein each of (2-,3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl),pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or3-thienyl), quinolinyl, naphthyl, or phenyl may be substituted by OR₁₄,OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉,NR₁₀C(Y′)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, orNR₁₀C(O)C(O)OR₁₄; R₈ is independently selected from hydrogen or R₉; R₉is C₁₋₄ alkyl optionally substituted by one to three fluorines; R₁₀ isOR₈ or R₁₁; R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substitutedby one to three fluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S; R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups unsubstituted or substitutedon the methyl with 1 to 3 fluoro atoms; R₁₄ is hydrogen or R₇; or whenR₈ and R₁₄ are as NR₈R₁₄ they may together with the nitrogen form a 5 to7 membered ring comprised of carbon or carbon and one or more additionalheteroatoms selected from O, N, or S; R₁₅ is C(O)R₁₄, C(O)NR₈R₁₄,S(O)_(q)NR₈R₁₄ or S(O)_(q)R₇ where q is 0, 1 or 2; provided that: (f) R₇is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines; or the pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein R₁ is —CH₂-cyclopropyl, —CH₂—C₅₋₆cycloalkyl, —C₄₋₆ cycloalkyl unsubstituted or substituted by OH,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or —C₁₋₂ alkylunsubstituted or substituted by 1 or more fluorines, and —(CH₂)₂₋₄ OH;R₂ is methyl or fluoro-substituted alkyl, and X is YR₂.
 3. A compoundaccording to claim 1 wherein R₁ is —CH₂-cyclopropyl, cyclopentyl,3-hydroxycyclopentyl, methyl or CF₂H; X is YR₂; Y is oxygen; X₂ isoxygen; and R₂ is CF₂H or methyl.
 4. A compound according to claim 1which iscis-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanol;trans-4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine;cis-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine;andtrans-4-[4-(2-Aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexyl-1-amine.5. A compound of Formula (II)

wherein: R₁ is —(CR₄R₅)_(n)C(O)O(CR₄R₅)_(m)R₆,—(CR₄R₅)_(n)C(O)NR₄(CR₄R₅)_(m)R₆, —(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆, or—(CR₄R₅)_(r)R₆ wherein the alkyl moieties unsubstituted or substitutedwith one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ andR₅ are independently selected hydrogen or C₁₋₂ alkyl; R₆ is hydrogen,methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃ alkyl, halosubstituted aryloxyC₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup; provided that: a) when R₆ is hydroxyl, then m is 2; or b) when R₆is hydroxyl, then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in—(CR₄R₅)_(n)O(CR₄R₅)_(m)R₆; X is YR₂, fluorine, NR₄R₅, or formyl amine;Y is O or S(O)_(m′); m′ is 0, 1, or 2; X₂ is O or NR₈; X₄ is H, R₉, OR₈,CN, C(O)R₈, C(O)OR₈, C(O)NR₈R₈, or NR₈R₈; R₂ is independently selectedfrom —CH₃ or —CH₂CH₃ optionally substituted by 1 or more halogens; s is0 to 4; Ar is phenyl unsubstituted or substitued by R₇; R₇ is—(CR₄R₅)_(q)R₁₂ or C₁₋₆ alkyl wherein: the R₁₂ or C₁₋₆ alkyl group isunsubstituted or substituted one or more times by methyl or ethylunsubstituted or substituted by 1-3 fluorines; —F; —Br; —Cl; —NO₂;—NR₁₀R₁₁; —C(O)R₈; —CO₂R₈; —O(CH₂)₂₋₄OR₈; —O(CH₂)_(q)R₈; —CN;—C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)NR₁₀R₁₁; —O(CH₂)_(q)C(O)R₉;—NR₁₀C(O)NR₁₀R₁₁; —NR₁₀C(O)R₁₁; —NR₁₀C(O)OR₉; —NR₁₀C(O)R₁₃;—C(NR₁₀)NR₁₀R₁₁; —C(NCN)NR₁₀R₁₁; —C(NCN)SR₉; —NR₁₀C(NCN)SR₉;—NR₁₀C(NCN)NR₁₀R₁₁; —NR₁₀S(O)₂R₉; —S(O)_(m′)R₉; —NR₁₀C(O)C(O)NR₁₀R₁₁;—NR₁₀C(O)C(O)R₁₀; or R₁₃; q is 0, 1, or 2; R₁₂ is R₁₃, OR₁₄, OR₁₅, SR₁₄,S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(Y′)R₁₄,NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄,NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉,NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄, or NR₁₀C(O)C(O)OR₁₄; or C₃-C₇cycloalkyl, or (2-, 3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl,(2- or 3-thienyl), quinolinyl, naphthyl, or phenyl, wherein each of (2-,3- or 4-pyridyl), pyrimidinyl, pyrazolyl, (1- or 2-imidazolyl),pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or3-thienyl), quinolinyl, naphthyl, or phenyl may be substituted by OR₁₄,OR₁₅, SR₁₄, S(O)_(m′)R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉,NR₁₀C(Y′)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(Y′)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR₁₀C(NCN)SR₉,NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄,orNR₁₀C(O)C(O)OR₁₄; R₈ is independently selected from hydrogen or R₉; R₉is C₁₋₄ alkyl optionally substituted by one to three fluorines; R₁₀ isOR₈ or R₁₁; R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substitutedby one to three fluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S; R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups unsubstituted or substitutedon the methyl with 1 to 3 fluoro atoms; R₁₄ is hydrogen or R₇; or whenR₈ and R₁₄ are as NR₈R₁₄ they may together with the nitrogen form a 5 to7 membered ring comprised of carbon or carbon and one or more additionalheteroatoms selected from O, N, or S; R₁₅ is C(O)R₁₄, C(O)NR₈R₁₄,S(O)_(q)NR₈R₁₄ or S(O)_(q)R₇ where q is 0, 1 or 2; provided that: (f) R₇is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines; or the pharmaceutically acceptable salts thereof.
 6. Acompound according to claim 5 wherein A compound according to claim 1wherein R₁ is —CH₂-cyclopropyl, —CH₂—C₅₋₆ cycloalkyl, —C₄₋₆ cycloalkylunsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or4-cyclopentenyl), benzyl or —C₁₋₂ alkyl unsubstituted or substituted by1 or more fluorines, and —(CH₂)₂₋₄ OH; R₂ is methyl orfluoro-substituted alkyl, and X is YR₂.
 7. A compound according to claim5 wherein A compound according to claim 1 or 2 wherein R₁ is—CH₂-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂H; Xis YR₂; Y is oxygen; X₂ is oxygen; and R₂ is CF₂H or methyl.
 8. Acompound according to claim 5 which is4-[4-(2-aminopyrimidin-5-yl)phenyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanone.9. A pharamceutical composition comprising a compound of claim 1 and apharamceutically acceptable excipient.
 10. A pharmaceutical compositioncomprising a compound of claim 5 and a pharmaceutically acceptableexcipient.
 11. A method for treating an inflammatory disease whichmethod comprises administering a compound according to claim 1 incombination with a pharamceutically acceptable excipient to a patient inneed thereof.